USPTO Patents Application 09993647

*■

Consommation

et Corporations Canada

Bureau des brevets

Ottawa, Canada
K1A 0C9

Consumer and
Corporate Affairs Canada

Patent Office

(21) (Al)
(22)
(43)
(52)

C . R . CL

2 , 028 , 536

1990/10/25

1991/04/28

167-211
167-244
167-265

Ul

to

GO

(51) INTL. CL . A61K-31/435; A61K-31/335; A61K-31/17

(19) (ca) APPLICATION FOR CANADIAN PATENT (12)

(54) Injectable Parasiticidal Composition

(72) Oechslein, Walter - Switzerland ;
Gehret, Jean-Claude - Switzerland ;
Hess, Ernst - Switzerland ;

(73) Ciba-Geigy AG - Switzerland ;
(30) (CH) 3898/89-4 1989/10/27

(57) 20 Claims

Notice: The specification contained herein as filed

Canada

CCA 3254 (10-39) 41

AP/5-17812/+

Iniectable parasiticidal composition
Abstract

Parenterally injectable compositions for controlling parasites, which compositions contain
from 0,1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a
1-substituted azacycloalkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant
or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of
an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent
or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic
solvents.

2028536

- 1 -

AP/5-17812/4-

Iniectable parasiticidal composition

The present invention relates to a composition for controlling parasites harmful to animals,
which composition is parenterally injectable and contains at least one sparingly soluble
benzoylphenylurea as active ingredient.

Injectable formulations are often the most favourable form of administration because even
small amounts of active ingredient can be dosed very accurately, they are easy to
administer and they cause negligible distress to the animals to be treated, especially
relatively large productive livestock, such as, for example, cattle, sheep, horses and
donkeys. When, however, sparingly soluble substances, such as, especially, benzoyl-
phenylureas, are used in the form of injectable formulations, problems occur in producing
an effective plasma level, that is to say, an even distribution of a sufficient amount of
active ingredient in the plasma, because the injected material is influenced by the tissue
fluid and, for example, the physico-chemical properties of the material can thus be so
changed that a considerable proportion of the injected material crystallises very rapidly
and, as a result, remains at the site of injection or very close thereto. For example,
benzoylureas, such as N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chloro-
phenyl]-N'-[2,6-difluorobenzoyl]-urea, can be dissolved in dimethyl sulfoxide and
N-methylpyrrolidone (approximately 35 %; here and hereinafter, percentages are
weight-per-volume percentages). Although those solutions are water-miscible, they have
the disadvantage that, when injected parenterally, a considerable amount of the injected
material is precipitated on contact with the tissue fluid, remains at the site of injection and
therefore contributes nothing to the achievement of as high a plasma level as possible.
The use of such solutions is therefore uneconomical and, especially in the case of animals
that are later to be slaughtered and used as food for animals or especially humans, is
possible only to a limited extent owing to the local concentration of injected material.

Surprisingly, it has now been found that, by the addition of 1- substituted
azacycloalkan-2-ones, it is possible to produce parenterally injectable formulations of
sparingly soluble benzoylphenylureas with which a very markedly increased
bioavailability is achieved. As a result, the high level of activity known per se of this class

-2-

of compound can be exploited even in this accurately dosable form of administrate. The
compositions according to the invention differ from conventional compositions in
advantageous manner in that the injected material is better

therefore considerably less material has to be injected to achieve an effect of the same
™ as in the case of conventional compositions, or in that, when the same amoun* of
^ve Ingredient are used, it is possible with the compositions accord ng to the ~
to maintain a high plasma level over a distinctly longer penod of tune than in the case
conventional compositions*

The present invention accordingly relates to a composition for controlling parasites, which
composition is parenterally injectable and contains

(a) from 0.1 to 10 %. preferably from 0.5 to 7 % and especially from 1 to 5 %, of at least
one benzoylphenylurea as active ingredient,

(b) from 0.1 to 60 %, preferably from 0.1 to 50 %. especially from 0.5 to 10 %. of a

1-substituted azacycloalkan-2-one, physiologically tolerable surfactant or

(c) from 2 to 90 %, preferably from 40 to 85 %, ot a pnysioiogicoi y

mixture of surfactants,

(d) if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer

of a physiologically tolerable hydrophilic solvent or mixture of solvents or a
mixture of physiologically tolerable hydrophilic and lipophilic solvents.

The above information is to be understood as meaning that component e) is always
present, that is to say, the sum of components a), b), c) and d) cannot be 100 %.

Advantageously, the type and amount of solvent is chosen first in accordance with the

S mixture ad 100 The solvent used to make up the amount may be

dissolve the active ingredient or may be a different solvent. The term solvent is also

used here to mean "mixture of solvents".

"Parenterally injectable" is to be understood within the scope of this invention *» ">"*«
thTrctmposition containing the dissolved active ingredient can be *^>T£
Zy subcutLously, inttamuscularly or intravenously, for examp e
the muscle tissue or into the blood vessels, by means of a cannula (injection syringe,

1

-3-

infusion, etc.). by-passing the gastro-intestinal tract.

Intramuscular and, especially, subcutaneous administration are preferred within the scope
of the present invention. According to the invention, it is possible to formulate and
administer any sparingly soluble benzoylphenylurea.

The preparation and mode of action of benzoylureas have already been described in
numerous publications, for example in PCT Patent Application WO 86/03941 and
European Patent Applications EP-0,079,311 and EP-0,179,022.

A group of benzoylphenylureas preferred within the scope of the present invention
consists of compounds of formula I

F>6

/ CO-t-X-J — CO — N-R 7 (I)

wherein

each of R x , R 2 , R3 and R 5 , independently of the others, is hydrogen, halogen, C r C 6 alkyl,
C r C 6 haloalkyl, d-Qalkoxy, CVQhaloalkoxy or Ci-Cgalkylthio;
R 4 is hydrogen, halogen, CVQalkyl, C a -C 6 haloalkyl, C 1 -C 6 alkoxy, d-Qhaloalkoxy,
C r C 6 alkylthio or NHR'; wherein R' is hydrogen, R 8 CO- or R9NHCO-, wherein R 8 is a
C r C 4 alkyl that is unsubstituted or mono- to tri-substituted by the same or different
substituents from the group halogen, C r C 4 alkoxy, C r C 4 acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R 9 is a C r C 4 -
alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;
Xis-NH-or -N e Y® ; wherein

Y® is an inorganic or organic cation;
R 6 is hydrogen or C x -C 6 alkyl; and

R 7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or
pyrazinyl, the substituents being selected from the series halogen, especially fluorine or
chlorine, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, alkylsulfmyl, alkylsulfonyl, haloalkylsulfinyl,
haloalkylsulfonyl, alkylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy,

-4-

each of which last two substituents is substituted by substituents from the group consisting
of halogen, haloalkyl, haloalkoxy and nitro, it being possible, in the case where R 7 is
substituted phenyl, for cyano, N'-n-propyl-N'-phenylureido, an -0-CF 2 -CF 2 -0- bridge
connecting two adjacent carbon atoms of the phenyl ring to one another, or phenoxy that is
substituted by an -0-CF 2 -CF 2 -0- bridge connecting two adjacent carbon atoms of the
phenyl ring to one another, also to be present as substituent (a phenyl ring that is
substituted by an -0-CF 2 -CF 2 -0- bridge connecting two adjacent ring carbon atoms to one
another forms a 2,2,3,3-tetrafluoro-l ,4-benzodioxane radical with said bridge).

Alkyl as substituent or as part of a substituent is, insofar as the number of carbon atoms is
not defined, preferably unbranched or branched C r C 6 alkyl, especially C r C 4 alkyl and
preferably methyl.

Alkenyl and alkynyl as substituents or parts of substituents have preferably from 3 to 5
carbon atoms, the multiple bond generally being separated from the rest of the molecule
by at least one carbon atom not participating in the multiple bond.

Halogen is to be understood as being fluorine, chlorine, bromine or iodine, but especially
fluorine or chlorine.

In connection with R 7 , substituents at the ring or ring system are especially alkyl,
haloalkyl, alkylthio, atkoxy and haloalkoxy groups which may be straight-chained or
branched and preferably have from 1 to 4 carbon atoms. Examples of such groups are,
inter alia, methyl, -CF 3 , methoxy, methylthio, -OCF 3 , ethyl, ethoxy, n-propyl,
-CF 2 -CHF-CF 3 , n-propoxy, -OCF 2 -CHF-CF3, isopropyl, isopropoxy, n-butyl, n-butoxy,
n-pentyl, n-pentyloxy, n-hexyl and n-hexyloxy.

Prominence should be given to compounds of formula I wherein

each of R u R 2 , R 3 and R 5 , independently of the others, is hydrogen, halogen, d-Qalkyl,
C r C 6 haloalkyl, C r C 6 alkoxy, CVQshaloalkoxy or C r C 6 alkylthio;
R 4 is hydrogen, halogen, Q-Qalkyl, C 1 -C 6 haloalkyl, Cj-Qalkoxy, C r C 6 haloalkoxy,
C r C 6 alkylthio or NHR*; wherein R* is hydrogen, R 8 CO or R9NHCO-, wherein R 8 is a
C r C 4 alkyl that is unsubstituted or mono- to tri-substituted by the same or different
substituents from the group halogen, C r C 4 alkoxy, C r C 4 acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R 9 is a C r C 4 -
alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;

2028538

-5-

X is -NH- or -N e Y® ; wherein

Y® is an inorganic or organic cation;
R 6 is hydrogen or C r C 6 alkyl; and

R 7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyriniidinyl or
pyrazinyl, the substituents being selected from the series halogen, especially fluorine or
chlorine, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,
haloalkylsulfonyl, alkylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy,
each of which last two substituents is substituted by halogen, haloalkyl, haloalkoxy or by
nitro.

Especially preferred are representatives of formula I wherein

each of R x and R 5 , independently of the other, is hydrogen, fluorine, chlorine, methoxy or
methylthio, especially fluorine;

R 3 is hydrogen or fluorine and R 4 is hydrogen or NH 2 ;
R 2 is hydrogen, fluorine or chlorine, especially hydrogen;
X is -NH- or -N° Y® ; wherein

Y® is Na®, K® or tetraalkylammonium, such as (n-C 4 H 9 ) 4 N® (CH 3 ) 4 N®, (C 2 H 5 ) 4 N®

or n-C 16 H 3 3-N®(CH 3 )3, but especially -NH-;

R 6 is hydrogen or C r C 3 alkyl, preferably hydrogen, and

R 7 is unsubstituted or, preferably, substituted phenyl,

the phenyl radical preferably being substituted by one or two halogen atoms, especially
fluorine or chlorine, and, additionally, either by C r C 6 haloalkoxy, especially C r C 3 halo-
alkoxy, or by 2-pyridyloxy, the 2-pyridyloxy radical for its part being preferably
substituted by CF 3 and halogen, especially CF 3 and fluorine or chlorine.

A further group of preferred benzoylphenylureas within the scope of formula 1 consists of
the following compounds of formula II

jrr— CONHCON*

N =\ (II)

-6-

wherein

R 4 is hydrogen or NH 2 ;

R 10 is hydrogen, halogen or methyl; and

R u is hydrogen or halogen.

A preferred sub-group is formed by compounds of formula II wherein
R 4 is hydrogen or NH 2 ;

R 10 is hydrogen, fluorine, chlorine or bromine; and
R n is hydrogen, fluorine, chlorine or bromine.

Especially preferred representatives of formula II are those wherein
R 4 is hydrogen or NH 2 ;

R 10 is 4-fluoro, 4-chloro, 4-bromo or 4-methyl; and
R n is chlorine.

The compounds in the following Table are especially preferred individual representatives
of compounds of formula II:

2028536

-i -

Table 1: Preferred benzovlphenvlureas of formula II

Compound no.

R,

R

10

R n m.p. [°C]

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

1.10

1.11

1.12

1.13

1.14

1.15

1.16

1.17

1.18

1.19

1.20

1.21

1.22

1.23

1.24

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

NH 2

4-CH 3

4-Br

4-CH3

4-F

4-C1

4-F

4-C1

H

H

4-Br

H

H

4-Br

4- CH3

5- CH3
5-CH3

5- CH3

6- CH3
6-F

6-C1

6-C1

6- CI

H

4-C1

CI

CI

H

CI

CI

H

H

CI

H

H

Br

I

Br

F

H

CI

F

CI

CI

CI

F

H

F

CI

178-
198-
188-
174-
185-
185-
185-
172-
186-

179
200
189
177
189
188
188
•173
■188

181-182

Preferred embodiments of the present invention contain as active ingredient one of the
benzoylphenylureas listed below, which list is not, however, exhaustive.

CONHCONH-

CI

^ ^— CONHCONH-^ ^ —

OCF3

- 8-

O

A

CONHCONH

-v>o- iFi

CI

CONHCONH

OCF 2 CHFCI

CI

CI

— ✓ js — CONHCONH — (\ ,) OCF 2 CHFCi

CI

CI

CONHCONH

\ A

ci

OCF 2 CHFCI

CONHCONH — /) CF 3

F
F

CI

CONHCONH

\ A

ci

OCF 2 CHFBr

CI

CI

o

^ ^— CONHCONH-

^ /^O

CF 2
I

CF 2

CI

CONHCONH

-9-

F CI

CH

N

CH 2 CH 2 CHg

CI

CI

^— CONHCONH—^ ^ OCF 2 CHF 2

CI

C!

CONHCONH — ^ ^

CI

-NHCON
I

CI

^3 H 7(n)

CI

CONHCONH-

O

CF 2 CFCI 2

CI
Ci

CONHCONH

OCF 2 CHFCF 3

CI

CI

CONHCONH

CI

CI

CONHCONH—^

N

CI

- 10-

- ii -

J^— CONCONH ^ ^ Na e

CI

CONCONH < x /) — OCF 3 K

F 0-CF 2

* (n-C 4 H 9 ) 4 N

CONCONH £ A

CI

CONCONH L \ — OCF 2 CHFCi (C 2 H 5 ) 4 N®

CI

OCF 2 CHFCF 3

CONCONH d J) OCF 2 CHFCI (n-C 4 H 9 ) 4 N

- 12-

CONCONH ^ ^ — CF 3 K®

^ ^— CONCONH OCF 2 CHFBr (n-C 4 H 9 ) 4 N®

CONCONH ^ \ OCF 2 CHFCF 3 (n-C 4 H 9 ) 4 N®

C!

e

CONCONH

F

c

Nae

CONCONH C \ O ^ \ O (n-C 4 H 9 ) 4 N®

<^V~ CONCONH °v (CH 3 ) 4 N e

^CF 2
0-CF 2

F CI

CONCONH /^V-N^ 3 (n-C 4 H 9 ) 4 N®

CH2CH2CH3

F CI

C

2023536

- 13-

G

CONCONH

NHCON
1

-O

(CH 3 ) 4 N

C 3 H 7(n>

CI

CONCONH

C!

CONHCONH

OCF 2 CHFCF 3

CI

CI

e

CONCONH

OCF 2 CHFCF 3 (n-C 4 H 9 ) 4 N

F
CI

CI
CI

e

e

CONCONH-

y ^ OCF 2 CHFCF 3 (C 2 H 5 ) 4 N

e

CI

CI

e

CONCONH-

X

(n-C 4 H 9 ) 4 N

- 14-

Cl pi

e

^ CONCONH ( N ^ (n-C 4 H 9 ) 4 N®

CI

e 7=^

CONCONH ^ U (CH 3 ) 4 N®

CI

0 N

^— CONCONH ^ N

©

~0
c*.

£ ^— CONCONH d /) K®

Especially preferred are formulations according to the invention that contain
N-[3K3-chloro-5-trifluoromethylpyri^

N'-[2,6-difluorobenzoyl]~urea or N-[3-(3-chloro-5-trifluoromethylp>Tidyl-2-oxy)-4-
chlorophenyll-N^P^-difluoro-S-aminobenzoyll-urea as active ingredient.

Within the scope of the present invention, 1 -substituted azacycloalkan-2-ones shall be
understood as being compounds of formula III

-R

(III)

wherein n is an integer from 2 to 7 and R is a C 6 -C 15 alkyl which may be interrupted by an
oxygen atom. R is preferably an unbranched C 10 -C 14 alkyl, especially n-dodecyl. Of the
1 -substituted azacycloaIkan-2-ones, l-n-dodecylazacycloheptan-2-one (Azone®) and
l-n-dodecylazacyclopentan-2-one are especially preferred.

2028536

-15-

The use of 1-substituted azacycloalkan-2-ones, including azone (Azone®), as penetration
enhancers in transdermal systems (penetration into and through the skin after topical
administration) is known, for example, from US 4 557 934 and the corresponding patent
publication EP 0 129 284. Those references describe the carrier function of 1-substituted
azacycloalkan-2-ones, which amounts to an improved penetration of the skin barrier in the
case of certain active ingredients. Japanese Patent Applications JP 63-002 923 and JP
61-263 914 disclose azone as a formulation auxiliary in preparations for controlling
tumours.

Within the scope of the present invention, suitable physiologically tolerable surfactants are
especially non-ionic surfactants.

Within the scope of the present invention, suitable physiologically tolerable surfactants are
especially non-ionic surfactants having a molecular weight of less than 20,000, preferably
less than 5,000, that belong to the group defined below:

(1) Polyethoxyiated triglycerides, (2) polyethoxylated hydroxy stearic acid esters, (3)
polyethoxylated sorbitan fatty acid esters, (4) sorbitan fatty acid esters, (5) poly-
ethoxylated methyl glucoside sesquistearates, (6) fatty acid sugar esters, (7)
polyethoxylated fatty alcohol ethers, (8) polyethoxylated fatty acid esters, (9)
polyethoxylated fatty acid amines and (10) polyethoxy/polypropoxy block polymers
[preferably block polymers having HLB values (HLB: hydrophilic-lipophilic balance) of
12-20],

Of the polyethoxylated triglycerides, hydroxystearic acid esters, sorbitan fatty acid esters,
methyl glucoside sesquistearates, fatty alcohol ethers, fatty acid esters and fatty acid
amines, mention may be made especially of those having from 2 to 100, especially from
10 to 40 and, more especially, 10, 20 or 40 ethylene oxide units.

Of the polyethoxy/polypropoxy block polymers, those having an ethylene oxide content of
from 20 to 80 % should be given prominence.

Especially suitable representatives of the group listed above are (EO -
oxide units):

number of ethylene

2028536

- 16-

(1) Polyethoxylated castor oil (EO 40), commercially available under the name

CREMOPHOR® EL (BASF AG);

Polyethoxylated, hydrogenated castor oil (EO 40, EO 60), commercially available
under the name CREMOPHOR® RH 40, RH60, (BASF AG);

(2) Polyethoxylated 12-hydroxystearic acid ester (EO 15), commercially available
under the name SOLUTOL® HS 15 (BASF);

(3) Polyethoxylated sorbitan monolaurate (EO 20), commercially available under the
name TWEEN® 20 (ICI);

Polyethoxylated sorbitan monopalmitate (EO 20), commercially available under
the name TWEEN® 40 (LCI);

Polyethoxylated sorbitan monostearate (EO 20), commercially available under the
name TWEEN® 60 (ICI);

Polyethoxylated sorbitan monooleate (EO 20), commercially available under the
name TWEEN® 80 (ICI);

Polyethoxylated sorbitan tristearate (EO 20), commercially available under the
name TWEEN® 65 (ICI);

Polyethoxylated sorbitan trioleate (EO 20), commercially available under the name
TWEEN® 85 (ICI);

(4) Sorbitan monolaurate, commercially available under the name SPAN® 20 (ICI);

Sorbitan monopalmitate, commercially available under the name SPAN® 40 (ICI);
Sorbitan monostearate, commercially available under the name SPAN® 60 (ICI);
Sorbitan monooleate, commercially available under the name SPAN® 80 (ICI);
Sorbitan tristearate, commercially available under the name SPAN® 65 (ICI);

2028536

- 17 -

Sorbitan trioleate, commercially available under the name SPAN® 85 (ICI);

Polyethoxylated methyl glucoside sesquistearate (EO 20), commercially available
under the name GLUCAMATE® SSE-20 (Amerchol Corp.);

12-hydroxy stearin saccharose ester,
saccharose rnonolaurate,
saccharose monomyristate,
saccharose monopalmitate,
saccharose monooleate,
saccharose monostearate,
saccharose distearate
saccharose dioleate,
saccharose dipalmitate,

Saccharose mono-/di-/tri-palmitate/stearate products are commercially available,
for example under the names

CRODESTA® DKS F10, F20, F50, F70, F110, F140, F160 (Croda Chemicals
Ltd.);

®

Saccharose monococoate, commercially available under the name CRODESTA
SL40 (Croda Chemicals Ltd.);

Polyethoxylated oleyl alcohol ether (EO 2), commercially available under the
names AMEROXOL® OE-2 (Amerchol Europe) and Brij 92 (Adas Chemie/ICI);

Polyethoxylated oleyl alcohol ether (EO 10), commercially available under the
names AMEROXOL® OE- 10 (Amerchol Europe) and Brij 96 (Adas Chemie/ICI);

Polyethoxylated oleyl alcohol ether (EO 20), commercially available under the
names AMEROXOL® OE-20 (Amerchol Europe) and Brij 98 (Atlas Chemie/ICI);

Polyethoxylated stearate (EO 8, EO 20, EO 30, EO 40*. EO 50, EO 100),
commercially available under the names Myrj® 45, 49, 51, (52, 52C, 52S)*, 53, 59

(ICI);

- 18 -

2028536

Polyethoxylated laurate (in the form of dilaurate) (EO 5, EO 10), commercially
available under the name Pegosperse® 200-DL (Glyco Inc.);

Polyethoxylated cocoate (EO 7), commercially available under the name
CETIOL® HE (Henkel Corp.);

(9) Polyethoxylated tallow fatty amine (EO 10), commercially available under the
name GENAMIN® T100 (Hoechst AG);

(10) Ethylene oxide/propylene oxide block polymer having a molecular weight of
approximately 16,000 and an ethylene oxide content of 80 %, commercially
available under the name PLURONIC® F-108 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of
approximately 4500 and an ethylene oxide content of 50 %, commercially
available under the name PLURONIC® P-85 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of
approximately 1450 and an ethylene oxide content of 20 %, commercially
available under the name PLURONIC® L-42 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of
approximately 2900 and an ethylene oxide content of 40 %, commercially
available under the names SYNPERONIC® PE L 64 (ICI) and Pluronic L 64
(BASF Wyandotte Corp.).

The above trade names for surfactants are to be understood as being only examples and
not limitations.

Within the scope of the present invention, the following surfactants (A to F) and mixtures
of surfactants (X to Z) have proved to be especially suitable:

A) Polyethoxylated castor oil (EO 40);

B) Polyethoxylated hydrogenated castor oil (EO 40);

C) Polyethoxylated 12-hydroxystearic acid ester (EO 15);

D) Polyethoxylated oleyl alcohol ether (EO 10);

2028536

- 19-

E) Polyethoxylated laurate (in the form of dilaurate; molecular weight 200, 400, EO 5,
EO 10);

F) Ethylene oxide/propylene oxide block polymer (molecular weight 2900, ethylene

oxide content 40 %);
X) Mixture of A) and B), preferably in the ratio A:B = 2: 1 to 1 :2, especially 1:1;
Y) Mixture of C) and E), preferably in the ratio of C:E = 2: 1 to 1 :2, especially 1:1;
Z) Mixture of A) and E), preferably in the ratio of A:E = 3 : 1 to 1 :2, especially 1 : 1 to

1.5:1..

Non-ionic surfactants, such as can be used within the scope of the present invention, are
known from standard works of the relevant literature. The following may be mentioned as
examples of such standard works:

Ash, M. and I., Encyclopedia of Surfactants, Chemical Publishing Co. Inc., New York,
N.Y. (Vol. I, 1980; Vol. H, 1981; Vol. Ill, 1981; Vol. IV, 1985);

1986 International McCutcheon's Emulsifiers & Detergents, The Manufacturing
Confectioner Publishing Co., Glen Rock, NJ, USA;

Stache, H., Tensid-Taschenbuch, Carl Hanser Verlag, Munich, Vienna, 1981.

Within the scope of the present invention, suitable physiologically tolerable hydrophilic
solvents are those belonging to the group listed below:

a) Monohydroxyalkyl groups having from 2 to 10 carbon atoms, b) acyclic saturated
polyols, c) dimethyl sulfoxide, d) glycerol formal, e) 2,2-dimethyl-4-hydroxymethyl-
1,3-dioxolane (solketal), f) tetrahydrofurfuryl alcohol (polyethoxy) ether (glycofurol), g)
water and h) N-methylpyrrolidone.

There may be mentioned as examples of representatives of sub-group a): ethanol,
1-propanol, 2-propanol, 2-butanol, tert.-butyl alcohol, 1-hexanol, 1-heptanol, 2-heptanol,
1-octanol, 2-octanol, 1-nonanol and 1-decanol.

Examples of representatives of sub-group b) are especially polyols having from 2 to 6,
preferably 3 or 4, carbon atoms and 2 or 3 hydroxy groups, such as 1 ^-propanediol,
glycerol, 1,2-butanediol, 1,3-butanediol and corresponding polyols etherifiedby lower

2028536

-20-

alkyl groups, especially methyl groups, such as, for example, 1,2-propanediol-l -methyl
ether, and, in addition, polyethylene glycols having an average molar mass in the range of
from 200 to 600, such as, for example, polyethylene glycol 300 (commercially available,
for example, under the name PLURIOL E300, BASF).

Suitable lipophilic solvents are especially esters of carboxylic acids, for example ethyl
acetate, n-propyl acetate and n-butyl acetate, and liquid waxes, such as, for example,
isopropyl myristate, isopropyl palmitate, lauric acid hexyl ester and ethyl oleate.

In the case of mixtures of hydrophilic and lipophilic solvents, the proportion of lipophilic
solvent is advantageously from 0.1 to 30 %, based on the total amount of solvent.

Within the scope of the present invention it is possible to use any surfactant and solvent
normally suitable for administration in veterinary medicine.

Acids suitable as stabilising component within the scope of this invention are especially
organic acids having from 3 to 6 carbon atoms. Examples of suitable acids are citric acid,
ascorbic acid, lactic acid, malic acid and tartaric acid.

Suitable as stabilising buffer mixtures are physiologically tolerable buffer mixtures
customarily used in human medicine or in veterinary medicine.

The preferred embodiments of the injectable parasiticidal compositions according to the
invention include, for example, the following compositions:

(A) From 0.1 to 10 % of a benzoylphenylurea, from 0.5 to 10 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(B) From 0.5 to 7 % of a benzoylphenylurea, from 0.5 to 10 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(C) From 1 to 5 % of a benzoylphenylurea, from 0.5 to 10 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

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(D) From 0.1 to 10 % of a benzoylphenylurea, from 0.1 to 50 % of a 1 -substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(E) From 0.5 to 7 % of a benzoylphenylurea, from 0.1 to 50 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(F) From 1 to 5 % of a benzoylphenylurea, from 0.1 to 50 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(G) From 0.1 to 10 % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(H) From 0.5 to 7 % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent;

(I) From 1 to 5 % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to
1 % of a stabiliser and ad 100 % of solvent.

Within the combinations (A) to (I), specific embodiments that are especially preferred are
those wherein the active ingredient is N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-

chlorophenyl]-N'-[2,6-difluorobenzoyl]-urea or N-[3-(3-chloro-5-
trinuoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluorc-3-aniinoben Z oyl]-ure^

Also especially preferred within the combinations (A) to (1) are those wherein the
1-substituted azacycloalkan-2-one is n-dodecylazacycloheptan-2-one or n-dodecyl-
azacyclopentan-2-one.

The present invention relates also to a process for the preparation of an injectable
composition for controlling parasites in and on productive livestock and domestic animals,

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which composition is paxenterally injectable and contains from 0.1 to 10 % of a
benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted azacyclo-
alkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of
surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a
buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture
of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents,
which process comprises dissolving the benzoylphenylurea in a hydrophilic solvent and
mixing the solution with the surfactant and the 1-substituted azacycloalkan-2-one, and, if
appropriate, with the lipophilic solvent and, if appropriate, with a stabiliser, making up the
batch with a solvent and sterile-filtering the resulting final mixture through a filter and
then subjecting it to heat sterilisation.

The injectable compositions according to the invention are effective against a large
number of parasites, especially against ectoparasites in and on domestic animals and
productive livestock, such as insects of the orders Homoptera, Heteroptera, Diptera,
Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Psocoptera and Hymenoptera and also
arachnida of the order Acarina, especially the sub-order Ixodida (ticks). The compositions
according to the invention also exhibit a good anthelmintic action. They are suitable for
controlling parasitic nematodes, for example of the orders Rhabditida, Ascaridida,
Spirurida and Trichocephalida, or for controlling cestodes of the orders Cyclophyllidae
and Pseudophillidae or for controlling trematodes of the order Digenea in domestic
animals and productive livestock.

Domestic animals and productive livestock are to be understood as being, for example,
cattle, sheep, goats, horses, pigs, cats and dogs.

The particular advantage of the compositions according to the invention resides in the fact
that they can be used systemically by administering them locally and thus spreading them
through the whole animal via the blood plasma and tissue fluid.

The present invention accordingly relates also to a method for the systemic control of
parasites in and on productive livestock and domestic animals, which comprises the
prophylactic or curative parenteral injection of the composition according to the invention
into the animal.

In addition, the present invention relates to the use of 1-substituted azacycloalkan-2-ones

2028

-23-

in benzoylphenylurea-based veterinary medicinal preparations for controlling endo- and
ecto-parasites.

Examples

Formulation of compositions according to the invention
Example F- 1 :

N-[3-(3-chloro-5-trifluoromethylpyridyl-
2-oxy)-4-chlorophenyl]-N' -[2,6-difluoro-

benzoyl]-urea 2 *^ S

polyethoxylated castor oil (EO 40) 400 S

dimethyl sulfoxide 20.0 g

lauric acid hexyl ester 5.0 g

n-dodecylazacycloheptan-2-one 5.0 S

n-propyl acetate ad 100 ml

Example F-2:

N-[3-(3-chloro-5-trifluoromethylpyridyl-
2-oxy)-4-chlorophenyl]-N , -[2,6-difluoro-

benzoyl]-urea 2 *^ g

polyethoxylated castor oil (EO 40) 400 2

dimethyl sulfoxide 200 g

lauric acid hexyl ester 50 8

n-dodecylazacycloheptan-2-one 100 S

n-propyl acetate ad 100 ^
Example F-3:

N-[3-(3-chloro-5-trifluoromethylpyridyl-

2- oxy )-4-chlorophenyl]-N ' -[2,6- difluoro-

3- aminobenzoyl]-urea 2 *^ g
polyethoxylated castor oil (EO 40) 40 0 S
dimethyl sulfoxide 20 0 g
lauric acid hexyl ester 5.0 g
n-dodecylazacycloheptan-2-one 5.0 g
n-propyl acetate ad 100 101

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Example F-4:

N-[3-(3-chloro-5-trifluoromethylpyridyl-

2- oxy )-4-chlorophenyl]-N ' -[2,6-difluoro-

3- aminobenzoyl]-urea 2 *^ g
polyethoxylated castor oil (EO 40) 40 -° 8
dimethyl sulfoxide 20 -° 8
lauric acid hexyl ester 5,0 g
n-dodecylazacycloheptan-2-one 10-0 g
n-propyl acetate ad 100 ml

Example F-5:

N-[3-(3-chloro-5-trifluoromethylpyridyl-
2-oxy)-4-chlorophenyl]-N'-[2 > 6-difluoro-

benzoyl]-urea 2 8

polyethoxylated castor oil (EO 40) 40.0 8

PEG-200 dilaurate 42 5 8

citric acid a25 8

n-dodecylazacycloheptan-2-one 5.0 g

N-methylpyrrolidone ad 100 ml

Biological Example

Bioavailability (plasma concentration)

In order to investigate bioavailability in vivo, formulations F-l to F-5 according to the
invention are each administered once subcutaneously to each of 4 cattle of from 200 to
300 kg body weight (BW) at a dose of 1 mg/kg BW. For comparison purposes, the control
group, consisting of 4 cattle, receives the active ingredient in the following formulation:

N-[3-(3-chloro-5-trifluoromethylpyridyl-
2-oxy)-4-chlorophenyl]-N*-[2,6-difluoro-

benzoyl]-urea ^ 8

polyethoxylated castor oil (EO 40) 400 8

PEG-200 dilaurate 42 * 5 8

N-methylpyrrolidone ad 100 ml

The plasma samples taken after specific intervals of time are analysed. Whereas the
formulations according to the invention achieve plasma concentrations in the range of

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from 50 to 100 ppb after 24 hours, the concentration of the active ingredient in the case of
the formulation not according to the invention is below that range by at least a factor of
two*

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What is claimed is :

L A composition for controlling parasites that attack productive livestock and domestic
animals, which composition is parenterally injectable and contains from 0.1 to 10 % of a
benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted
azacycloalkan-2-one, from 2 to 90 % of a physiologic ally tolerable surfactant or mixture
of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or
a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or
mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic
solvents.

2. A composition according to claim 1, which contains compounds of formula 1

*6

CO-Hh X -1 — CO — N - R 7 (I)

wherein

each of Rj, R 2 , R 3 and R 5 , independently of the others, is hydrogen, halogen, C^Cgalkyl,
C r C 6 haloalkyl, CVQalkoxy, CVQhaloalkoxy or d-Cfialkylthio;
R 4 is hydrogen, halogen, C r C 6 alkyl, Ci-Cfihaloalkyl, d-Qjalkoxy, CVQhaloalkoxy,
C!-C 6 alkylthio or NHR'; wherein R' is hydrogen, R 8 CO- or R9NHCO-, wherein R 8 is a
C r C 4 alkyl that is unsubstituted or mono- to tri-substituted by the same or different
substituents from the group halogen, d-Qalkoxy, C 1 -C 4 acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R 9 is a C r C 4 -
alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;
Xis-NH-or -N e Y e ; wherein

Y® is an inorganic or organic cation;
R 6 is hydrogen or C x -C 6 alkyl; and

R 7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or
pyrazinyl, the substituents being selected from the series halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkyl-
sulfinyl, alkylsulfonyl, haloalkylsulfmyl, haloalkylsulfonyl, alkylamino, dialkylamino and
benzyl and also phenoxy or pyridyloxy, each of which last two substituents is substituted

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by substituents from the group consisting of halogen, haloalkyl, haloalkoxy and nitro, it
being possible, in the case where R 7 is substituted phenyl, for cyano, N'-n-propyl-N'-
phenylureido, an -0-CF 2 -CF 2 -0- bridge connecting two adjacent carbon atoms of the
phenyl ring to one another, or phenoxy that is substituted by an -0-CF 2 -CF 2 -0 bridge
connecting two adjacent carbon atoms of the phenyl ring to one another, also to be present
as substituents

3. A composition according to claim 2, wherein

each of R a , R 2 , R 3 and R 5 , independently of the others, is hydrogen, halogen, Q-Qalkyl,
C r C 6 haloalkyl, C r C 6 alkoxy, C r C 6 haloalkoxy or Q-Cgalkylthio;
R 4 is hydrogen, halogen, CVQalkyl, CVCghaloalkyl, CVQalkoxy, C r C 6 haloalkoxy,
C 1 -C 6 alkylthio or NHR'; wherein R* is hydrogen, R 8 CO- or R9NHCO-, wherein R g is a
C 1 -C 4 alkyl that is unsubstituted or mono- to tri-substituted by the same or different
substituents from the group halogen, Q-Qalkoxy, C r C 4 acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R 9 is a CVC4-
alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;
X is NH- or -N e Y® ; wherein

Y® is an inorganic or organic cation;
R 6 is hydrogen or CVC^alkyl; and

R 7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or
pyrazinyl, the substituents being selected from the series halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkyl-
sulfmyl, alkylsulfonyl, haloalkylsuMnyl, haloalkylsulfonyl, alkylamino, dialkylamino and
benzyl and also phenoxy or pyridyloxy, each of which last two substituents is substituted
by halogen, haloalkyl, haloalkoxy or by nitro.

4. A composition according to claim 2, wherein

each of R x and R 5 , independently of the other, is hydrogen, fluorine, chlorine, methoxy or
methylthio;

R 3 is hydrogen or fluorine and R4 is hydrogen or NH 2 ;
R 2 is hydrogen, fluorine or chlorine;
Xis-NH-or -N e Y® ; wherein

Y® is Na®, K® or tetraalkylammonium, such as (n-C 4 H 9 ) 4 N®, (CH 3 ) 4 N®, (C 2 H 5 ) 4 N®

or n-C 16 H 33 -N®(CH 3 )3;

R 6 is hydrogen or C r C 3 alkyl, and

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R 7 is unsubstituted phenyl or phenyl substituted by one or two halogen atoms and,
additionally, by Cj-C^haloalkoxy or by 2-pyridyloxy, the 2-pyridyloxy radical for its part
being substituted by CF 3 and halogen.

5. A composition according to claim 1, which contains compounds of formula II

wherein

R 4 is hydrogen or NH 2 ;

R 10 is hydrogen, halogen or methyl; and

R u is hydrogen or halogen.

6. A composition according to claim 5, wherein
R 4 is hydrogen or NH 2 ;

R 10 is hydrogen, fluorine, chlorine or bromine; and
R n is hydrogen, fluorine, chlorine or bromine.

7. A composition according to claim 5, wherein
R 4 is hydrogen or NH 2 ;

R 10 is 4-fluoro, 4-chloro, 4-bromo or 4-methyl; and
R n is chlorine*

8. A composition according to claim 1, which contains N-[3-(3-chloro-5-trifluoromethyl-
pyridyl-2-oxy)-4-chlorophenyl]-N , -[2,6-difluorobenzoyl]-urea as active ingredient.

9. A composition according to claim 1, which contains N-[3-(3-chloro-5-trifluoromethyl-
pyridyl-2-oxy)-4-chlorophenyl]-N , -[2,6-difluoro-3-aminobenzoyl]-urea as active

ingredient.

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10. A composition according to claim 1, wherein the 1 -substituted azacycloalkan-2-one is
a compound of formula III

(CH 2 ) n N-R

c ( m >

II

o

wherein n is an integer from 2 to 7 and R is a C 6 -C 15 alkyl which may be interrupted by an
oxygen atom.

11. A composition according to claim 1 that contains n-dodecylazacycloheptan-2-one.

12. A composition according to claim 1 that contains n-dodecylazacyclopentan-2-one.

13. A composition according to claim 8 that contains n-dodecylazacycloheptan-2-one.

14. A composition according to claim 8 that contains n-dodecylazacyclopentan-2-one.

15. A composition according to claim 1 that contains dimethyl sulfoxide as hydrophilic
solvent.

16. A composition according to claim 1 that contains N-methylpyrrolidone as hydrophilic
solvent.

17. A composition according to claim 1 that contains a lipophilic solvent from the group
consisting of esters of carboxylic acids and liquid waxes.

18. A composition according to claim 1 that contains as stabilising component an acid
selected from the group consisting of citric acid, ascorbic acid, lactic acid, malic acid and
tartaric acid.

19. A process for the preparation of a composition for controlling parasites that attack
productive livestock and domestic animals, which composition is parenterally injectable

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and contains from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to
60 % of a 1-substituted azacydoalkan-2-one, from 2 to 90 % of a physiologically tolerable
surfactant or mixture of surfactants and, if appropriate, as stabilising component, from
0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable
hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable
hydrophilic and lipophilic solvents, which process comprises dissolving the benzoyl-
phenylurea in a hydrophilic solvent and mixing the solution with the surfactant and the
1-substituted azacycloalkan-2-one, and, if appropriate, with the lipophilic solvent and, if
appropriate, with a stabiliser, making up the batch with a solvent and sterile-filtering the
resulting final mixture through a filter and then subjecting it to heat sterilisation.

20. A method of controlling parasites that attack productive livestock and domestic
animals, which method comprises injecting parenterally into the host organism attacked
by parasites a composition containing from 0.1 to 10 % of a benzoylphenylurea as active
ingredient, from 0.1 to 60 % of a 1-substituted azacycloalkan-2-one, from 2 to 90 % of a
physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as
stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a
physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of
physiologically tolerable hydrophilic and lipophilic solvents.

\*.r if i V-j V 1? Ci * V.

Patent Agents

SUBSTITUTE

REM PL A CEMENT

SECTION is not Present

Cette Section est Absente